This invention relates to compounds and methods for the treatment or prevention of pain or nociception.
Pain causes a great deal of suffering and is a sensory experience distinct from sensations of touch, pressure, heat and cold. It is often described by sufferers by such terms as bright, dull, aching, pricking, cutting or burning and is generally considered to include both the original sensation and the reaction to that sensation. This range of sensations, as well as the variation in perception of pain by different individuals, renders a precise definition of pain difficult. Where pain is xe2x80x9ccausedxe2x80x9d by the stimulation of nociceptive receptors and transmitted over intact neural pathways, this is termed nociceptive pain. Pain may also be caused by damage to neural structures, and pain is often is manifested as neural supersensitivity; this type of pain is referred to as neuropathic pain.
The level of stimulation at which pain is perceived is referred to as the xe2x80x9cpain thresholdxe2x80x9d. Where the pain threshold is raised, for instance, by the administration of an analgesic drug, a greater intensity or more prolonged stimulus is required before pain is experienced. Analgesics are a class of pharmaceutical agent which, following administration to a patient in need of such treatment, relieve pain without loss of consciousness. This is in contrast to other pain-relieving drugs, for example, general anaesthetics which obtund pain by producing a hiatus in consciousness, or local anaesthetics which block transmission in peripheral nerve fibres thereby preventing pain.
Tachykinin antagonists have been reported to induce antinociception in animals, which is believed to be analogous to analgesia in man (for review see Maggi et al, J. Auton. Pharmacol. (1993) 13, 23-93). In particular, non-peptide NK-I receptor antagonists have been shown to produce such analgesia, thus, for example, in classical tests of chemo-nociception (phenylbenzoquinone-induced writhing and formalin test) the NK-1 receptor antagonist RP 67,580 produced analgesia with potency comparable to that of morphine (Garret et al, Proc. Natl. Acad. Sci. USA (1993) 88, 10208-10212).
Opioid analgesics are a well-established class of analgesic agents. These compounds are generally accepted to include, in a generic sense, all drugs, natural or synthetic, with morphine-like actions. The synthetic and semi-synthetic opioid analgesics are derivatives of five chemical classes of compound: phenanthrenes; phenylheptylamines; phenylpiperidines; morphinans; and benzomorphans. Pharmacologically these compounds have diverse activities, thus some are strong agonists at the opioid receptors (e.g. morphine); others are moderate to mild agonists (e.g. codeine); still others exhibit mixed agonist-antagonist activity (e.g. nalbuphine); and yet others are partial agonists (e.g. nalorphine). Whilst an opioid partial agonist such as nalorphine, (the N-alkyl analogue of morphine) will antagonise the analgesic effects of morphine, when given alone it can be a potent analgesic in its own right. Of all of the opioid analgesics, morphine remains the most widely used and is a suitable archetype compound. Unfortunately, apart from its useful therapeutic properties, morphine also has a number of drawbacks including respiratory depression, decreased gastrointestinal motility (resulting in constipation) and, in some individuals, nausea and vomiting may occur. Another characteristic is the development of tolerance and physical dependence which may limit the clinical use of such compounds.
Anti-inflammatory compounds directed at blocking or reducing synovial inflammation, and thereby improving function, and analgesics directed to reducing pain, are presently the primary method of treating the rheumatoid diseases and arthritis. Aspirin and other salicylate compounds are frequently used in treatment to interrupt amplification of the inflammatory process and temporarily relieve the pain. Other drug compounds used for these purposes include phenylpropionic acid derivatives such as Ibuprofen and Naproxin, Sulindac, phenyl butazone, corticosteroids, antimalarials such as chloroquine and hydroxychloroquine sulfate, and fenemates. For a thorough review of various drugs utilized in treating rheumatic diseases, reference is made to J. Hosp. Pharm., 36:622 (May 1979).
Calcium channels are membrane-spanning, multi-subunit proteins that allow controlled entry of Ca++ ions into cells from the extracellular fluid. Such channels are found throughout the animal kingdom, and have been identified in bacterial, fungal and plant cells. Commonly, calcium channels are voltage dependent. In such channels, the xe2x80x9copeningxe2x80x9d allows an initial influx of Ca++ ions into the cells which lowers the potential difference between the inside of the cell bearing the channel and the extracellular medium bathing the cell. The rate of influx of Ca++ ions into the cell depends on this potential difference. All xe2x80x9cexcitablexe2x80x9d cells in animals, such as neurons of the central nervous system (xe2x80x9cCNSxe2x80x9d), peripheral nerve cells, and muscle cells, including those of skeletal muscles, cardiac muscles, and venous and arterial smooth muscles, have voltage-dependent calcium channels. Calcium channels are physiologically important because the channels have a central role in regulating intracellular Ca++ ions levels. These levels are important for cell viability and function. Thus, intracellular Ca++ ion concentrations are implicated in a number of vital processes in animals, such as neurotransrmitter release, muscle contraction, pacemaker activity, and secretion of hormones.
It is believed that calcium channels are relevant in certain disease states. A number of compounds useful in treating various cardiovascular diseases in animals, including humans, are thought to exert their beneficial effects by modulating functions of voltage-dependent calcium channels present in cardiac and/or vascular smooth muscle. Many of these compounds bind to calcium channels and block, or reduce the rate of, influx of Ca++ ions into the cells in response to depolarization of the cell membrane. An understanding of the pharmacology of compounds that interact with calcium channels in other organ systems, such as the central nervous system, and the ability to rationally design compounds that will interact with these specific subtypes of human calcium channels to have desired therapeutic, e.g., treatment of neurodegenerative disorders, effects have been hampered by an inability to independently determine how many different types of calcium channels exist or the molecular nature of individual subtypes, particularly in the CNS, and the unavailability of pure preparations of specific channel subtypes, i.e., systems to evaluate the specificity of calcium channel-effecting compounds.
Multiple types of calcium channels have been detected based on electrophysiological and pharmacological studies of various mammalian cells from various tissues (e.g., skeletal muscle, cardiac muscle, lung, smooth muscle and brain) Bean, B. P., Annu Rev. Physiol. 51:367-384 (1989) and Hess, P., Annu. Rev. Neurosci. 56:337 (1990). These different types of calcium channels have been broadly categorized into four classes, L-, T-, N-, and P-type, distinguished by current kinetics, holding potential sensitivity and sensitivity to calcium channel agonists and antagonists. Four subtypes of neuronal voltage-dependent calcium channels have been proposed Swandulla, D. et al., Trends Neurosci 14:46 (1991). The L-, N- and P-type channels have each been implicated in nociception, but only the N-type channel has been consistently implicated in acute, persistent and neuropathic pain. A synthetic version of xcexa9-conotoxin MVIIA, a 25-amino acid peptide derived from the venom of the piscivorous marine snail, Conus magus has been used intrathecally in humans and has xcx9c85% success rate for the treatment of pain with a greater potency than morphine.
While known drug therapies have utility, there are drawbacks to their use. For instance, it may take up to six months of consistent use of some medications in order for the product to have effect in relieving the patient""s pain. Consequently, a particular subject may be receiving treatment and continuing to suffer for up to six months before the physician can assess whether the treatment is effective. Many existing drugs also have substantial adverse side effects in certain patients, and subjects must therefore be carefullly monitored. Additionally, most existing drugs bring only temporary relief to sufferers and must be taken consistently on a daily or weekly basis for continued relief. Finally, with disease progression, the amount of medication needed to alleviate the pain may increase thus increasing the potential for side effects. Thus, there is still a need for an effective and safe treatment to alleviate pain.
In one aspect the present invention provides compounds having selective action at N-type calcium channels that are useful for the treatment of pain.
Compounds of the present invention that show selective action at N-type calcium channels are compounds in accord with structural diagram I, 
wherein:
R1 is NE1E2 where E1 is selected from hydrogen and methyl and E2 is selected from hydrogen, C1-4alkyl and phenylC1-4alkyl;
R2 is selected from E3 and E4, wherein:
E3 is selected from C1-6alkyl, C1-4alkoxy and C1-6alkoxyC1-4alkyl; and
E4 is phenyl substituted with a moiety selected from halogen, C1-4alkyl, C1-4alkoxy, perfluoroC1-2alkyl and C5-7cycloalkyl;
R3 is selected from E5 and E6, wherein:
E5 is selected from NH2, perfluoroC1-2alkyl, C1-6alkyl, C1-6alkoxyC1-4alkyl, phenylC1-2alkoxy and phenoxyC1-2alkyl; and
E6 is phenyl substituted at one or two positions with moieties independently selected from halogen, cyano, perfluoroC1-2alkyl, C1-4alkoxy, phenylC1-2alkoxy, phenoxyC1-2alkyl, C1-6alkoxyC1-4alkyl.
Particular compounds of the invention are those wherein:
R1 is NE1E2 where E1 is hydrogen and E2 is selected from hydrogen, methyl and benzyl;
R2 is selected from E3 and E4, wherein:
E3 is selected from methyl, pentyl, propoxymethyl; and
E4 is phenyl substituted with a moiety selected from fluoro, chloro, methyl, methoxy, trifluoromethyl and cyclohexyl;
R3 is selected from E5 and E6, wherein:
E5 is selected from methyl, pentyl, trifluoromethyl, propoxymethyl, benzyloxy and phenyloxymethyl; and
E6 is phenyl substituted at one or two positions with moieties independently selected from chloro, fluoro, butyl, trifluoromethyl, methoxy, ethoxy, benzyloxy, phenoxymethyl, propoxymethyl and cyano.
Most particular compounds of the invention are those exemplified herein.
In another aspect, the invention comprises a method for using compounds according to structural diagram I for the treatment of pain, said method comprising administering a pain-ameliorating effective amount of any such compound.
One embodiment of the method of the invention comprises administering a pain-ameliorating effective amount of a compound in accordance with structural diagram I to a subject in need of treatment for acute, persistent or neuropathic pain.
In a further aspect, the invention comprises methods for making compounds in accord with structural diagram I.
In yet another aspect, the invention comprises pharmaceutical compositions comprising compounds in accord with structural diagram I together with excipients, diluents or stabilisers, as further disclosed herein, useful for the treatment of acute, persistent and neuropathic pain.